Loss of Dsg2 Promotes Tumorigenesis in Pancreatic Cancer Cells through ERK Activation

Abstract

The ability to maintain cell‐cell adhesion is crucial for tissue integrity and organization. Accordingly, loss of cohesiveness plays a critical role in cancer invasion and metastasis. Desmosomes are cell junctions providing strong intercellular adhesive strength and dysregulation of desmosomal constituents was shown to contribute to cancer progression through altered cell signaling pathways.Here, we focused on the cadherin‐type adhesion molecules desmoglein 2 (Dsg2) and desmocollin 2 (Dsc2), building up the desmosomal core. siRNA‐mediated knock down of Dsg2 but not Dsc2 resulted in loss of cell cohesion and enhanced migration of pancreatic adenocarcinoma cells (AsPC‐1). We established stable Dsg2 knockdown cell lines in which loss of Dsg2 caused an increase in cell migration and enhanced invasion through extracellular matrix without influencing cell proliferation.To identify potential pathways regulated by Dsg2, we screened major kinases and detected the activity of ERK to be significantly enhanced in Dsg2‐deficient cells. Consequently, inhibition of ERK phosphorylation in Dsg2 knockdown cells led to normalized migration. Interestingly, loss of Dsg2 was accompanied with reduced levels of the desmosomal adapter protein and transcriptional regulator plakoglobin, whereas other desmosomal molecules were not altered. Consistent with this observation, in initial experiments overexpression of plakoglobin rescued enhanced migration induced by silencing of Dsg2. These results indicate that loss of Dsg2 promotes tumorigenic behavior of pancreatic cancer cells by regulation of ERK activity and the levels of plakoglobin.